Recent Publications
Kufreobong E Inyang 1, Christine M Evans 1, Matthew Heussner 1 2, Margaret Petroff 3, Mark Reimers 1, Paola D Vermeer 4, Nathan Tykocki 5, Joseph K Folger 1, Geoffroy Laumet
Severe pain is often experienced by patients with head and neck cancer and is associated with a poor prognosis. Despite its frequency and severity, current treatments fail to adequately control cancer-associated pain because of our lack of mechanistic understanding. Although recent works have shed some light of the biology underlying pain in HPV-negative oral cancers, the mechanisms mediating pain in HPV+ cancers remain unknown. Cancer-derived small extracellular vesicles (cancer-sEVs) are well positioned to function as mediators of communication between cancer cells and neurons. Inhibition of cancer-sEV release attenuated pain in tumor-bearing mice. Injection of purified cancer-sEVs is sufficient to induce pain hypersensitivity in naive mice that is prevented by QX-314 treatment and in Trpv1-/- mice. Cancer-sEVs triggered calcium influx in nociceptors, and inhibition or ablation of nociceptors protects against cancer pain. Interrogation of published sequencing data of human sensory neurons exposed to human cancer-sEVs suggested a stimulation of protein translation in neurons. Induction of translation by cancer-sEVs was validated in our mouse model, and its inhibition alleviated cancer pain in mice. In summary, our work reveals that HPV+ head and neck squamous cell carcinoma-derived sEVs alter TRPV1+ neurons by promoting nascent translation to mediate cancer pain and identified several promising therapeutic targets to interfere with this pathway.
https://pubmed.ncbi.nlm.nih.gov/37678566/
Geoffroy Laumet
The peripheral somatosensory system and the immune system share numerous characteristics, both working to sense external and internal environments to protect the organism from potential threats. Numerous studies over the past decade have revealed the contribution of somatosensory neuron–immune cell cross talk to allergy and immunity.
https://www.sciencedirect.com/science/article/pii/S0091674923014793?via%3Dihub
Sabrina de Souza , Jesús Rosario-Claudio , Jaewon Sim , Kufreobong E. Inyang , Andrew Dagenais , Karli Monahan , Beenhwa Lee , Hariharan Ramakrishnan , Visha Parmar , Matan Geron , Grégory Scherrer , Joseph K. Folger , Geoffroy Laumet
Appropriate regulation of the inflammatory response is essential for survival. Interleukin-10 (IL-10), a well-known anti-inflammatory cytokine, plays a major role in controlling inflammation. In addition to immune cells, we previously demonstrated that the IL-10 receptor (IL-10R1) is expressed in dorsal root ganglion sensory neurons. There is emerging evidence that these sensory neurons contribute to immunoregulation, and we hypothesized that IL-10 signaling in dorsal root ganglion (DRG) neurons facilitates the regulation of the inflammatory response. We showed that mice that lack IL-10R1 specifically on advillin-positive neurons have exaggerated blood nitric oxide levels, spinal microglia activation, and cytokine upregulation in the spinal cord, liver, and gut compared to wild-type (WT) counterparts in response to systemic lipopolysaccharide (LPS) injection. Lack of IL-10R1 in DRG and trigeminal ganglion (TG) neurons also increased circulating and DRG levels of proinflammatory C–C motif chemokine ligand 2 (CCL2).Interestingly, analysis of published scRNA-seq data revealed that Ccl2 and Il10ra are expressed by similar types of DRG neurons; nonpeptidergic P2X purinoceptor (P2X3R + ) neurons. In primary cultures of DRG neurons, we demonstrated that IL-10R1 inhibits the production of CCL2, but not that of the neuropeptides substance P and calcitonin-gene related peptide (CGRP). Furthermore, our data indicate that ablation of Transient receptor potential vanilloid (TRPV)1 + neurons does not impact the regulation of CCL2 production by IL-10. In conclusion, we showed that IL-10 binds to its receptor on sensory neurons to downregulate CCL2and contribute to immunoregulation by reducing the attraction of immune cells by DRG neuron-derivedCCL2. This is the first evidence that anti-inflammatory cytokines limit inflammation through direct binding to receptors on sensory neurons. Our data also add to the growing literature that sensory neurons have immunomodulatory functions.
https://pubmed.ncbi.nlm.nih.gov/38081433/
Guffey, H. E., Mrocko, A. L., Smith, B. K., & Spranger, M. D.
Oral demonstration of knowledge is an effective learning and assessment strategy. It has been shown that generating explanations to oneself, or self-explaining, can improve student understanding of information. This can be achieved via student-generated videos. The quantitative effects of student-generated videos on learning and assessment in postsecondary education are unknown. To our knowledge, this is the first study to analyze the effects asynchronous student-generated videos have on student learning and assessment in a large-enrollment (∼400 students), undergraduate physiology course. Students were charged with making self-generated videos discussing major physiological concepts and uploading these videos to Flip for assessment. Flip is an online, social education platform for asynchronous video-based discussion. In the present study, we combined four semesters (n = 1,100 students) of Flip data and analyzed the effects it had on student examination performance. Specifically, we first analyzed how students performed on exam questions corresponding to their Flip prompts in comparison to students not assigned those prompts [25/44 (57%) were statistically significantly different]. Second, we analyzed the association between Flip prompt score and performance on corresponding exam questions [39/44 (89%) were statistically significantly different]. Third, we analyzed the association between cumulative Flip score and performance on all corresponding, and noncorresponding exam questions. Finally, we analyzed the association between cumulative Flip score and averaged exam performance. There was a positive association (r = 0.54). Taken together, our data suggest that asynchronous student-generated Flip videos can facilitate student learning and assessment in a large-enrollment, undergraduate physiology course.NEW & NOTEWORTHY Oral demonstration of knowledge is an effective learning and assessment strategy. Student-generated videos have been shown to improve learning and assessment in secondary education. To our knowledge, this is the first study to analyze the effects asynchronous student-generated Flip videos have on student learning and assessment in postsecondary education. The results of the present study suggest that asynchronous student-generated Flip videos can facilitate student learning and assessment in a large-enrollment (∼400 students), undergraduate physiology course.
https://doi.org/10.1152/advan.00181.2022
Abdelgied M, Uhl K, Chen OG, Schultz C, Tripp K, Peraino AM, Paithankar S, Chen B, Tamae Kakazu M, Castillo Bahena A, Jager TE, Lawson C, Chesla DW, Pestov N, Modyanov NN, Prokop J, Neubig RR, Uhal BD, Girgis RE, Li X.
Idiopathic Pulmonary Fibrosis (IPF) is a pathological condition of unknown etiology which results from injury to the lung and an ensuing fibrotic response that leads to thickening of the alveolar walls and obliteration of the alveolar space. The pathogenesis is not clear and there are currently no effective therapies for IPF. Small airway disease and mucus accumulation are prominent features in IPF lungs, similar to Cystic Fibrosis (CF) lung disease. The ATP12A gene encodes the alpha-subunit of the non-gastric H+, K+-ATPase, which functions to acidify the airway surface fluid and impairs mucociliary transport function in cystic fibrosis patients. We hypothesize that the ATP12A protein may play a role in the pathogenesis of IPF. Our studies demonstrate that ATP12A protein is overexpressed in distal small airways from IPF patient lungs compared to normal human lungs. In addition, overexpression of the ATP12A protein in mouse lungs worsened the bleomycin (BLEO)-induced experimental pulmonary fibrosis. This was prevented by a potassium-competitive proton pump blocker, vonoprazan (VON). This data supports the concept that the ATP12A protein plays an important role in the pathogenesis of lung fibrosis. Inhibition of the ATP12A protein has the potential as a novel therapeutic strategy in IPF.